Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials

Objectives To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD). Methods We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events. Results Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as "high risk" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was "low risk". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies. Conclusions A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.


Introduction
Major depressive disorder (MDD) is a chronic psychiatric disorder common in older adults characterized by failure to achieve remission despite appropriate treatment with first-line antidepressant medications.MDD could not only reduce quality of life and burden the healthcare system, it may also increase the risk of death [1,2].The definition of Treatment-resistant depression (TRD) has not been agreed upon.The most popular saying at the moment is that TRD is defined as depression that remains unresolved despite two adequate trials of antidepressant drugs [3].It has been reported that treatment failure of depression may be related to several risk factors such as impaired mental health, disability, and cognitive decline [4][5][6][7][8].Significantly higher hospitalization rates and medical costs have been observed in patients with TRD and MDD patients compared with other patients [9].The treatment strategies for TRD and MDD mainly includes augmentation and switching.The former refers to adding another drug to the existing antidepressant treatment, while the latter refers to replacing the existing antidepressant medication with another drug from different class [10].
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial have revealed that augmenting treatment with bupropion or switching to bupropion was not inferior and may even be superior to other management strategies for patients with TRD or MDD [11].In addition, in the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial, augmentation treatment with Aripiprazole (A-ARI) and augmentation treatment with bupropion (A-BUP) was more effective than switching to bupropion (S-BUP) [12], which is consistent with the findings of an open-label randomized controlled trials (RCT) involving elderly MDD patients aged 60 years or older published recently [10].Nevertheless, which antidepressant treatment strategy has better efficacy and safety for patients with MDD has not yet reached a unified conclusion in all clinical trials.In 2017, Cheon et al. conducted a randomized, prospective, open-label clinical trial to directly compare the efficacy and safety between treatment with aripiprazole and augmentation treatment with bupropion, which found that augmentation treatment with aripiprazole and augmentation treatment with bupropion had similar efficacy and safety in patients with MDD [13].
Thus, we reported the first and largest systematic review and meta-analysis of RCTs to compare the efficacy and safety of the three most commonly used alternative treatment strategies (A-ARI, A-BUP, and S-BUP) for patients with TRD or MDD.

Inclusion and exclusion criteria
Articles were eligible when meeting the following standards: (1) study design was RCT; (2) studies were performed in patients with TRD or MDD; (3) studies evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching; (4).The study evaluated at least one efficacy (change of Montgomery-Asberg Depression Rating Scale (MADRS).The response rate and remission rate) or safety (adverse events and serious adverse events) and evaluated the outcome; (5) complete data to analyze risk ratio (RR) and weighted mean difference (WMD).We excluded study protocols, unpublished studies, non-original studies (including letters, comments, abstracts, corrections, and replies), non-RCT studies, studies without sufficient data, and reviews.

Data abstraction
The study assigned two authors to conduct data abstraction (Mengjia Ji and Junfei Feng).Any differences were settled by another author (Guirong Liu).We abstracted following information from eligible RCTs: first author name, published year, research period, study region, study design, treatment allocation, sample size, follow-up time, age, gender, education, age at first onset of major depressive disorder (MDD), the Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, Patient Health Questionnaire-9 (PHQ-9), Clinical Global Impression-Severity (CGI-S), change of MADRS, response rate, remission rate, adverse events and serious adverse events.If the article presented continuous data as median plus range or median plus interquartile range (IQR), we reanalyzed the mean ± standard deviation (SD) via the methods reported by Wan et al. and Luo et al. [15,16].If the research data is insufficient, corresponding authors were contacted for complete data.

Quality assessment
The quality assessment of eligible RCTs was conducted following the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0based on seven terms: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias [17].Three evaluation outcomes were assigned to every study aspect: low, high, and unclear risk.Studies with more "low risk" bias evaluations were regarded as superior.Two authors (Mengjia Ji and Junfei Feng) assessed the quality of all included studies, and any disagreement was resolved through discussion and ultimately by Guirong Liu's decision.

Sensitivity analysis and publication bias
We performed a sensitivity analysis for the results of adverse events of A-ARI vs. A-BUP and the remission rate of A-ARI vs. S-BUP to assess the effect of each RCT on the total WMD or RR via excluding eligible RCTs one by one.Sensitivity analysis found that the new total RR remained stable after removing each RCT for adverse events of A-ARI vs. A-BUP (Fig 8A).However, when we released the study reported by Lenze et al. [10], Mohamed

. Forest plots of adverse events in (A) A-ARI vs. A-BUP, (B) A-ARI vs. S-BUP, and (C) A-BUP vs. S-BUP).
https://doi.org/10.1371/journal.pone.0299020.g006et al. [12], or Yoon et al. [19], the pooled analysis of the remission rate of A-ARI vs. S-BUP changed from significant to nonsignificant (Fig 8B).After excluding the data reported by Cheon et al. [13], the heterogeneity of adverse events of A-ARI vs A-BUP reduced from 52% to 0%, suggesting that this paper may be the leading cause of the significant heterogeneity in the adverse events of A-ARI vs A-BUP.Besides, after excluding the data reported by Zisook et al. [20], the heterogeneity of the remission rate of A-ARI vs. S-BUP reduced from 59% to 0%, suggesting that this article may be the leading cause of the significant heterogeneity.Funnel plots revealed no considerable asymmetry was detected for all outcomes (Fig 9).

Discussion
In 2015, approximately 16.1 million adults in the United States were reported to suffer from MDD [12] since less than one-third of patients reported remission on their first course of drug therapy.As a result, many patients develop TRD after undergoing multiple regimens of antidepressant therapy.The experience after several unsuccessful treatments not only brought different degrees of adverse reactions to patients but also dealt a blow to patients' confidence in treatment.It caused them double pain.Therefore, finding a treatment plan with less adverse reactions and high remission rate is urgent.Approximately 10.8 million Americans with MDD could profit from alternative treatments each year [21,22].For these patients, a majority of clinical guidelines recommend switching or augmentation treatment with another antidepressant or a non-antidepressant [23].The most = common of these management strategies is changing to bupropion or augmentation treatment with bupropion or Aripiprazole [24].However, which treatment is more effective and has fewer adverse effects is still unclear.This study is the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with TRD or MDD.It can help provide more effective and appropriate treatment options for patients with MDD or TRD, improving their quality of life.
In this meta-analysis, we evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with TRD or MDD, and there were three key findings.First, there was no significant difference in remission rate, improvement of MADRS, adverse events, and serious adverse events between augmentation treatment with aripiprazole and augmentation treatment with bupropion.However, augmentation treatment with Aripiprazole had a significantly higher response rate than augmentation treatment with bupropion.This

Funnel plots of (A) adverse events for A-ARI vs. A-BUP, (B) remission for A-ARI vs. A-BUP, (C) serious adverse events for A-ARI vs. A-BUP, (D) remission for A-ARI vs. S-BUP, (E) serious adverse events for A-ARI vs. S-BUP, (F) remission for A-BUP vs. S-BUP, and (G) serious adverse events for A-BUP vs. S-BUP.
https://doi.org/10.1371/journal.pone.0299020.g009result was consistent with the findings reported by Mohamed et al. in 2017 [12].Second, augmentation treatment with Aripiprazole had a significantly higher remission rate compared with switching to bupropion.
Meanwhile, augmentation treatment with Aripiprazole and switching to bupropion have similar adverse events and serious adverse events.This finding is consistent with the results of most previous RCTs [10,12,19].The results showed that in both TRD and MDD patients, augmentation treatment with Aripiprazole improved depression more than augmentation treatment with bupropion or switching to bupropion.The reasons for the analysis may be as follows: Different from bupropion, and Aripiprazole is an atypical antipsychotic drug which can selectively stimulate the serotonin 1A receptor and effectively block the serotonin 2A receptor.It has the effect of stabilizing dopamine and can eliminate adverse emotions such as depression.Analysis of severe events found no significant difference, confirming that augmentation treatment with Aripiprazole is more appropriate for patients with TRD or MDD.
It should be noted that a study reported by Zisook et al. [20] found that augmentation treatment with Aripiprazole and switching to bupropion have similar remission rates, which is a secondary analysis of the VAST-D trial to compare the three management strategies during the continuation phase.Third, augmentation treatment with bupropion had a significantly higher remission rate compared with switching to bupropion.Besides, augmentation treatment with bupropion and switching to bupropion have similar adverse events and serious adverse events.Therefore, they can adjust the dosage of bupropion according to the patient's condition, which can effectively improve the remission rate of depression.A two-step, openlabel RCT involving elderly TRD patients aged 60 years or older reported by Lenze et al. [10] observed a similar finding.Still, several other studies found no significant difference in response rates between augmentation treatment with bupropion and switching to bupropion [12,19,20].
However, we must acknowledge several limitations of this meta-analysis.Firstly, the RCTs included in our study had different interventions (different initial and maintenance doses of antidepressants), which may be one of the sources of heterogeneity.Secondly, given none of the trials included in this meta-analysis were placebo-controlled, we could not demonstrate whether any of the three management strategies was better than no change in drug therapy.Thirdly, most of the studies included had a follow-up period of less than one year, and we could not confirm whether longer switching or augmentation treatment would have different efficacy or risks.Fourthly, only bupropion and Aripiprazole were evaluated in this meta-analysis, and the generalizability of the findings to other drugs is unclear.Finally, most of the included studies were from the USA, and whether similar findings exist in populations from other countries and regions is unknown.Despite several limitations of this meta-analysis, we conducted the first and largest meta-analysis of RCTs to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with TRD.The results of this meta-analysis validated the superiority of the augmentation treatment with Aripiprazole for patients with TRD reported by previous studies.More large-scale, multi-center, double-anonymized RCTs are needed to confirm our findings further.

Conclusion
Meta-analyses revealed that augmentation treatment with Aripiprazole may be a better comprehensive antidepressant treatment strategy than augmentation treatment with bupropion or switching to bupropion for patients with TRD and MDD.More large-scale, multi-centre, double-blind RCTs are needed to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies further.

Fig 9 .
Fig 9. Funnel plots of (A) adverse events for A-ARI vs. A-BUP, (B) remission for A-ARI vs. A-BUP, (C) serious adverse events for A-ARI vs. A-BUP, (D) remission for A-ARI vs. S-BUP, (E) serious adverse events for A-ARI vs. S-BUP, (F) remission for A-BUP vs. S-BUP, and (G) serious adverse events for A-BUP vs. S-BUP.